Our studies have focused on determining the molecular basis of alpha-1- antitrypsin (alpha-1AT) deficiency, the study of neonatal alpha-1AT serum levels and the identification of alpha-1AT deficient individuals for study in the alpha-1AT Deficiency Registry. In the past year we have identified four novel alpha-1AT variants. These include Pduarte, Pst. louis, Nullnew hope and Nullwest. Pduarte, an alpha-1AT allele associated with liver disease in a single individual, is the result of two amino substitutions, R101H and D256V. Pst. louis, another variant with a similar isoelectric point as Pduarte, is a normal variant which is the result of two amino acid substitutions, R101H and M222R. Alpha-1AT Nullwest is the first example of Null alpha-1AT allele that results from a RNA splicing error. Nullwest is the result of G->T in the splice donor site of exon II of the alpha-1AT gene. Alpha-1AT Nullnew hope is a particularly interesting mutation which occurs on the genetic background of the most common allele associated with profound alpha-1AT deficiency, PI*Z. Nullnew hope is the result of two amino acid substitutions, G320E and E342K (the PI*Z substitution). In addition to identification of new alpha-1AT mutants, the lab has investigated the molecular basis of the Nullclayton variant, a newly described alpha-1AT allele associated with a premature termination codon. Recent studies of COS I cells transfected with the Nullclayton variant has demonstrated that a small portion of the alpha-1AT Nullclayton protein escapes intracellular degradation only to be cleared in the extracellular milieu. Evaluation of 200 neonatal serum specimens has revealed that neonates have significantly reduced alpha-1AT levels as compared to adults. Furthermore, a sizable proportion of the neonatal population studied have alpha-1AT levels below the heterozygous alpha-1AT level associated with profound deficiency in adults. Finally, serving as the reference alpha-1AT phenotyping laboratory for the alpha-1AT Deficiency Registry, the lab has identified 328 profoundly deficient individuals throughout the USA and Canada.